REVIEW
Alzheimer’s disease CSF biomarkers: clinical indicationsand rational use
Ellis Niemantsverdriet1• Sara Valckx1
• Maria Bjerke1• Sebastiaan Engelborghs1,2
Received: 20 April 2017 / Accepted: 12 July 2017 / Published online: 27 July 2017
� The Author(s) 2017. This article is an open access publication
Abstract This review focusses on the validation and
standardization of Alzheimer’s disease (AD) cerebrospinal
fluid (CSF) biomarkers, as well as on the current clinical
indications and rational use of CSF biomarkers in daily
clinical practice. The validated AD CSF biomarkers, Ab1-
42, T-tau, and P-tau181, have an added value in the (dif-
ferential) diagnosis of AD and related disorders, including
mixed pathologies, atypical presentations, and in case of
ambiguous clinical dementia diagnosis. CSF biomarkers
should not be routinely used in the diagnostic work-up of
dementia and cannot be used to diagnose non-AD
dementias. In cognitively healthy subjects, CSF biomarkers
can only be applied for research purposes, e.g., to identify
pre-clinical AD in the context of clinical trials with
potentially disease-modifying drugs. Therefore, biomarker-
based early diagnosis of AD offers great opportunities for
preventive treatment development in the near future.
Keywords Alzheimer’s disease � Cerebrospinal fluid �Biomarkers � Dementia � Amyloid-b � Tau
Introduction
The Alzheimer continuum: a new concept
that has an impact on diagnosis, prevention,
and treatment strategies
The most common type of dementia is Alzheimer’s disease
(AD), affecting up to 60–70% of dementia cases and
exponentially increasing in prevalence with age. AD has a
long pre-clinical phase, in which neuropathological chan-
ges develop, starting at least a decade before symptom
onset. At onset, complaints are insidious and mild. Sub-
jective cognitive decline (SCD) refers to cognitive symp-
toms that cannot be confirmed by a neuropsychological
assessment. Patients who show subtle deficits in perform-
ing daily activities in combination with objective cognitive
dysfunction, confirmed by neuropsychological assessment,
have reached a stage of the so-called mild cognitive
impairment (MCI). If MCI is due to AD, a progressive
cognitive deterioration can lead to certain functional defi-
cits which characterize the AD dementia stage with a
progression rate of 20–40% in MCI patients [1–4].
Therefore, AD is described as a continuum and includes a
pre-clinical phase, SCD [5], MCI [6], and dementia due to
AD [7]. In the past, the diagnosis of AD could only be
suggested when the dementia stage was reached. Due to
major advances in biomarker-based research, it is now
possible to detect AD-related changes well before the onset
of the first clinical symptoms. This provides researchers an
exceptional window for early diagnosis, treatment, and
prevention strategies. The cerebrospinal fluid (CSF) offers
a window to the brain as the brain’s metabolism and
pathology is reflected in the CSF that can easily be col-
lected through a lumbar puncture (LP), which is a safe and
well-tolerated procedure [8, 9]. This review focusses on the
Joint last authors: Maria Bjerke, Sebastiaan Engelborghs.
& Sebastiaan Engelborghs
1 Reference Center for Biological Markers of Dementia
(BIODEM), Laboratory of Neurochemistry and Behavior,
Institute Born-Bunge, University of Antwerp (UAntwerp),
Antwerp, Belgium
2 Department of Neurology and Memory Clinic, Hospital
Network Antwerp (ZNA) Middelheim and Hoge Beuken,
Antwerp, Belgium
123
Acta Neurol Belg (2017) 117:591–602
DOI 10.1007/s13760-017-0816-5
validation and standardization of AD CSF biomarkers, as
well as on the current clinical indications and rational use
of CSF biomarkers in daily clinical practice.
The diagnosis of Alzheimer’s disease relies
on different biomarker categories: amyloid-Bdeposition, neurofibrillary tangles, and neuronal
degeneration
The clinical diagnosis of AD is often made in accordance
with the criteria from the National Institute of Neuro-
logical and Communicative Disorders and Stroke—Alz-
heimer’s Disease and Related Disorders Association
(NINCDS-ADRDA), originating from 1984 [10]. These
criteria are mainly based on excluding other systemic and
brain disorders that could account for cognitive deterio-
ration confined to the dementia stage and result at best in
a diagnosis of probable AD. A clinical diagnosis of
probable AD based on these criteria has been shown to
achieve an average sensitivity and specificity of 81 and
70%, respectively [11]. A promising tool to increase the
diagnostic accuracy of AD is the use of CSF biomarkers
[7, 12–14] that can be measured in the CSF after an LP.
If performed correctly, LP has a low complication rate, a
high diagnostic yield, and is usually more tolerable than
subjects expect [8, 9]. Biomarkers that reflect the
pathology of AD already show abnormal concentrations
in the pre-clinical stage of AD, thus allowing early AD
diagnosis [15], even before the onset of symptoms. In
1998, a consensus report was published by the Working
Group on Molecular and Biochemical Markers of Alz-
heimer’s Disease that determined the requirements for an
ideal diagnostic biomarker for AD [16]. In general,
biomarkers should be able to detect a fundamental feature
of AD pathology. The value of biomarkers should also be
demonstrated in neuropathologically confirmed subjects as
neuropathology is still considered the gold standard for
AD diagnosis. Diagnostic accuracy, sensitivity, and
specificity levels should be above 80%. The test itself
should be reliable and reproducible, non-invasive, simple
to perform, and inexpensive [16].
CSF biomarkers are preferred over blood/plasma bio-
chemical markers in AD to reflect brain pathophysiology,
because the brain (interstitial fluid) is in direct contact
with the CSF by unrestricted bi-directional flow of pro-
teins and the CSF is secluded from direct impact of the
peripheral system through the restricted transportation of
molecules and proteins by the blood–CSF barrier [17].
Therefore, CSF analysis is valuable to detect markers of
neurodegenerative diseases in vivo. CSF biomarkers are
related to the three main pathological changes that occur
in the AD brain (Table 1): amyloid-b (Ab) deposition into
extracellular Ab plaques, intracellular neurofibrillary tan-
gles (NFT) formation, and neuronal loss. The b-amyloid
peptide composed of 42 amino acids (Ab1-42) is the result
of the cleavage of transmembrane amyloid precursor
protein (APP) by b- and c-secretases. Ab1-42 is highly
insoluble and aggregates into extracellular Ab deposits in
the AD brain, detected as decreased CSF Ab1-42 con-
centrations in AD. Tau proteins are abundantly present in
the cytosol of neurons, where they function to stabilize
microtubules. In AD, an imbalance between kinases and
phosphatases results in a hyperphosphorylation of tau,
which leads to detachment of tau from microtubules and
to its accumulation into NFT. During the neurodegener-
ative process, tau and phosphorylated tau proteins are also
released into the extracellular space, resulting in increased
CSF tau concentrations in AD. The formation of plaques
and NFT promotes neuronal injury and, consequently,
neuronal and synaptic degeneration in AD. The first Abplaques occur at least 10 years, and probably 20–30 years
before the first symptoms [18], and are as such
detectable in the CSF for early diagnosis. CSF tau
biomarkers change later in the pathophysiological process
compared to CSF Ab1-42 [19, 20] and CSF tau is stronger
correlated with cognitive decline than Ab1-42 [20, 21].
CSF biomarkers give a complete overview of AD
pathophysiology, and in addition, an LP is highly acces-
sible with a low cost price, in contrast to the imaging-
based markers used in AD diagnosis (Table 1). These
imaging-based biomarkers include positron emission
tomography (PET) with amyloid-specific probes (marker
for Ab deposition) or tau tracers (marker for neuronal
injury), quantification of decreased metabolism in affected
brain regions with fluorodeoxyglucose (FDG) PET
imaging (marker for neuronal injury), quantification of the
brain perfusion in affected brain regions with single
photon emission computed tomography (SPECT) (marker
for neuronal injury), and the analysis of volumetric
magnetic resonance imaging (MRI) with determination of
hippocampal or medial temporal lobe atrophy (marker for
neuronal injury) [22–25].
A lot of progress has been made over the past decades to
improve AD diagnosis and to validate AD CSF biomarkers
in autopsy-confirmed dementia patients [26], resulting in
biomarker-based research diagnostic criteria as a growing
body of evidence shows that AD CSF biomarkers are
reliable, reproducible, and valid as well as suitable for cut-
off scores, sensitive, and specific for AD (differential)
diagnosis [13]. Therefore, revised criteria of both the
National Institute on Aging/Alzheimer’s Association
(NIA–AA) [7, 12, 14] and the International Working Group
(IWG) [13] include CSF AD biomarkers in the clinical
diagnostic work-up.
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Combining biomarkers to increase diagnostic accuracy
CSF Ab1-42 (marker for Ab deposition), total tau protein
(T-tau; marker for neuronal injury), and phosphorylated tau
at threonine 181 (P-tau181; marker for NFT) are validated
and integrated CSF biomarkers in the revised diagnostic
criteria of AD [7, 12–14, 27]. Changes in these three core
CSF biomarkers allow diagnosing AD already in its pro-
dromal stage [28]. Having all three biomarkers in the
normal range rules out AD. Intermediate conditions require
further patient follow-up [29]. The concentration of Ab1-42
decreases over time in AD subjects, while P-tau181 and
T-tau concentrations increase in AD patients compared to
healthy controls (including patients with psychiatric dis-
orders like depression) [27]. These biomarker changes
almost reach their maximum in the beginning of the
symptomatic phase of AD, limiting their predictive value
for cognitive decline [30]. The combined use of Ab1–42,
T-tau, and P-tau181, each essential in the biomarker panel,
has the highest diagnostic power to discriminate between
AD and cognitively healthy controls [13, 26], with a sen-
sitivity and specificity reaching 92 and 89%, respectively
[31]. Another model based on Ab1-42 and T-tau was
developed that could accurately discriminate AD from
controls by means of a discrimination line, which has been
validated in clinical practice [32] and in autopsy-confirmed
patients with sensitivity levels of 100% and specificity of
91% [26].
Diagnostic accuracy is independent from the analytical
platform
CSF Ab and tau proteins can be measured reliably with
several analytical techniques such as single-analyte ELI-
SAs or multi-analyte tests based on xMAP technology.
Multiple studies have shown that the diagnostic accuracy
of the CSF biomarker concentrations is similar when ana-
lytes are measured by means of a multi-analyte assay or
single-analyte ELISA tests [33, 34]. These studies show
that the clinical value of biomarkers is independent of the
method by which concentrations are determined.
The Alzheimer’s disease cerebrospinal fluidbiomarker panel
Standardization and harmonization efforts
Much effort has been put in the standardization and har-
monization of AD CSF biomarker analysis and interpre-
tation. The overall goal of all these projects is (1) to detect
AD at the earliest stage possible and identify ways to track
the disease through biomarkers, (2) to support advances in
AD intervention, prevention, and treatment (through new
diagnostic methods), and (3) to centralize data access.
The EU Joint Programme Neurodegenerative Disease
Research (JPND) consortium ‘Biomarkers for AD and
Parkinson’s Disease (PD)’ (BIOMARKAPD) Project
(2012–2015) aimed in developing certified reference
materials to harmonize assays by reducing inter-variability
across international centers [35]. In this regard, the BIO-
MARKAPD project has united many European countries
and Canada, to investigate complications related to the LP
procedure in a large prospective multi-center feasibility LP
study [8]. Such studies led amongst others to consensus LP
guidelines to minimize risks and maximize diagnostic gain
[9]. Another example of a standardization initiative is the
Global Biomarkers Standardization Consortium (GBSC),
with the goal to gather key researchers, clinicians, and
industry, regulatory and government leaders in AD to
achieve consensus on the best ways to standardize and
validate biomarker tests for use in clinical practices around
the world [27, 36]. In addition, the AD Neuroimaging
Initiative (ADNI), the Alzheimer Biomarker Standardiza-
tion Initiative (ABSI), and the JPND BIOMARKPD con-
sortium have been launched. The Alzheimer’s Association
Table 1 Overview of the
different biomarkers based on
the neuropathological changes
in Alzheimer’s disease
Pathological change Biomarker category Biomarker(s)
Ab deposition = early marker Biochemical (CSF)
Molecular imaging
CSF Ab1-42 or Ab1-42/Ab1-40
PET with amyloid-specific probes
NFT formation Biochemical (CSF) CSF P-tau181
Neuronal injury = downstream Biochemical (CSF)
Topographical
CSF T-tau
[18F]FDG-PET
SPECT
HCV / MTL atrophy on MRI
Ab amyloid-b, Ab1-42 b-amyloid peptide of 42 amino acids, CSF cerebrospinal fluid, FDG fluo-
rodeoxyglucose, HCV hippocampal volume, MTL medial temporal lobe, MRI magnetic resonance imaging,
PET positron emission tomography, P-tau181 phosphorylated tau at threonine 181, SPECT single photon
emission computed tomography, T-tau total tau protein
Acta Neurol Belg (2017) 117:591–602 593
123
launched an international external Quality Control (AA
QC) program (2009) [36], coordinated by the Clinical
Neurochemistry Laboratory in Molndal, Sweden, and has
put forth the aim to standardize CSF biomarker analyses
and monitor analytical variability for Ab and tau proteins
in CSF between both research and clinical laboratories
[34]. Unfortunately, the overall variability remained too
high to allow assignment of universal biomarker cut-off
values [36]. Further standardization of laboratory proce-
dures and improvement of operator performance is
required.
The running international standardization and harmo-
nization efforts are very valuable as these initiatives are
essential to ensure reproducible and consistent biomarker
measurements, to reduce discussion in the AD field
regarding biomarker values and clinical interpretation of
the biomarker results, and to facilitate worldwide com-
parison of CSF biomarkers.
Contributions and relevance of standardization
and harmonization efforts
The overall goal of all these projects is (1) to detect AD at
the earliest stage possible and identify ways to track the
disease through CSF biomarkers, (2) to support advances in
AD intervention, prevention, and treatment (through new
diagnostic methods), and (3) to centralize data access.
These initiatives have led to consensus publications on the
procedure for LP/CSF sampling [9], standardization of pre-
analytical factors [34, 37–39], immunoassay method vali-
dation and standardization for specific biomarkers
[35, 40, 41], and the clinical use of AD CSF biomarkers
[29, 42, 43].
One of the most important recommendations with a
significant effect on pre-analytical variability concerns the
standardization of the vial in which CSF is collected and
shipped to the reference lab. It was already well known that
adsorption of Ab1-42 on a glassy or polystyrene vial wall
causes false-low Ab1-42 values. Therefore, the use of
polypropylene vials is indispensable, but differences due to
adsorption of Ab1-42 may also occur between different
brands of polypropylene vials [38, 44, 45].
Importantly, although pre-analytical and analytical
variations in the concentration of CSF AD biomarkers are
kept to a minimum by means of these initiatives, a recent
study pointed out that simulated biomarker variability by
means of shifts of ±20% in one of the three core CSF
biomarkers has limited impact on the clinical accuracy of
AD CSF biomarkers in MCI and autopsy-confirmed AD
patients when using the IWG-2 criteria [46].
Clinical indications for using the Alzheimer’sdisease cerebrospinal fluid biomarker panel
To increase the diagnostic accuracy in case
of suspected Alzheimer’s disease
Although AD diagnostics increasingly become bio-
marker-based, this does not imply that every patient with
suspected AD needs an LP with the exception of patients
with early-onset dementia, in whom LP and CSF bio-
marker analysis should be routinely performed [29].
Indeed, evidence from memory clinic-based studies using
autopsy-confirmed dementia patients demonstrated that
the diagnostic accuracy of CSF biomarkers was compa-
rable to the diagnostic accuracy of a clinical diagnostic
work-up performed in demented patients consisting of a
semi-structured interview with patient and main care-
giver, general physical and clinical neurological exami-
nation, blood analysis, extensive neuropsychological
examination, and brain imaging [47, 48]. However, CSF
biomarkers are very valuable in those cases in which the
clinical diagnostic work-up is not able to discriminate
between AD and another (non-AD) type of dementia
[47, 48]. Therefore, in cases with an inconclusive clinical
diagnostic work-up, leading to an ambiguous AD versus
non-AD differential diagnosis, the AD CSF biomarker
panel has an added diagnostic value. This is as well
reflected by a growing number (from 238 in 2004 to
[1000 in 2016) of CSF samples that have been referred
to the UAntwerp BIODEM lab, specifically for this
indication [49].
To diagnose Alzheimer’s disease in its earliest stages
Pre-clinical Alzheimer’s disease
The neuropathological brain lesions are present in pre-
clinical AD, which is reflected by altered levels of the AD
CSF biomarkers already before the onset of symptoms, and
Ab1-42 is the earliest marker to mirror these changes
[18, 50]. This is of major importance to the health care
system given the pending availability of disease-modifying
drugs. Even though a CSF AD profile is much more
common in patients with MCI and SCD, it is also seen in
28–36% of cognitively healthy elderly at the age of 85
[15, 50]. However, in the absence of any therapeutic con-
sequences for pre-clinical AD, CSF biomarker analyses
should not be performed in asymptomatic subjects, except
in consented subjects and within the context of research
and clinical trials.
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Prodromal Alzheimer’s disease
Patients with MCI will progress to dementia at a much
higher rate than healthy elderly, which makes this an
excellent study population to explore the possible predic-
tive value of CSF biomarkers [51]. In these patients, the
three CSF biomarkers Ab1-42, T-tau, and P-tau181 are
strongly associated with future development of AD
dementia, which was proven in a large prospective study
with a mean follow-up period of more than 5 years [28] as
well as in two multi-center studies [52, 53]. The AD CSF
biomarkers can in fact identify those MCI patients who
have prodromal AD. In the study of Hansson et al., the
combination of CSF Ab1-42 and T-tau at baseline yielded
sensitivity and specificity levels of 95 and 83% for clinical
AD diagnosis in patients with MCI [17, 28]. A high pro-
gression rate (prodromal to dementia) was confirmed by
patients with a high likelihood for AD based on the NIA–
AA criteria compared to patients with an intermediate or
lowest likelihood for AD in a clinical setting [53].
To discriminate Alzheimer’s disease from other
neurodegenerative and cerebrovascular brain
disorders: differential diagnosis
The assessment of Ab1-42, T-tau, and P-tau181 can dis-
criminate between AD and non-AD dementias [26, 54], but
they cannot be used to confirm another type of dementia.
Several other brain diseases can lead to pathological values
of these core AD CSF biomarkers which might lead to
possible misinterpretation of the biomarker results in the
absence of clinical information. An increase in T-tau is also
detected after stroke [55] and in disorders with extensive
and/or rapid neuronal degeneration, such as Creutzfeldt–
Jakob’s disease (CJD) [56], as opposed to other disorders
with limited neuronal degeneration. For this reason,
P-tau181 seems to be a more specific marker for AD [54].
Moreover, both Ab1-42 and T-tau are detected at interme-
diate levels, in between normal control and abnormal AD
values [26, 27, 57, 58], in non-AD patients, especially in
dementia with Lewy bodies (DLB) but also in frontotem-
poral dementia (FTD), vascular dementia (VaD), and CJD.
To improve the discriminatory power for the differential
diagnosis of dementia, additional markers, more specific to
the non-AD dementia can be valuable, described below
(New biomarkers specific for non-AD diseases). Another
problem in using CSF biomarkers for dementia diagnosis is
the inter-patient variability. Indeed, heterogeneity in the
amount of plaques and tangles in AD brains exist, and the
plaque and tangle load in selected neocortical areas are
even known to correlate with CSF biomarker concentra-
tions, but not with Braak stages that take into account
neocortical as well as allocortical brain regions [59, 60].
To identify Alzheimer’s disease in case of suspected
mixed brain pathologies
The existence of co-pathologies can lead to a potential
misinterpretation of CSF biomarker results. It has been
confirmed in a neuropathological study that many
dementia patients have brain pathologies associated with
more than one type of dementia [61]. In case of non-AD
dementias, such as DLB, AD co-pathology frequently
occurs [62]. Furthermore, as age is a common risk factor
for neurodegenerative dementias and cerebrovascular
disease (CVD), many demented patients show signs of co-
pathologies on structural brain imaging at the clinical
diagnostic work-up, which is confirmed by neuropatho-
logical examination [61]. It is often difficult to judge
whether the vascular lesions are main contributors to the
dementia, and there is a risk of over diagnosing VaD
based on structural brain imaging [63]. In case of doubt
between VaD or mixed AD–CVD pathology in dementia
patients, the determination of CSF Ab1-42, T-tau, and
P-tau181 levels is of help to confirm or exclude the AD
component in the pathophysiology of the dementia syn-
drome [58].
To diagnose Alzheimer’s disease in case of a typical
presentations
AD is thought to progress in a fairly stereotypical manner,
as brain dysfunction begins in the hippocampal region
resulting in episodic memory loss as the first and most
typical symptom of AD [13]. However, there is consider-
able heterogeneity in the relative involvement of different
cognitive domains, and therefore, the IWG-2 criteria [13],
combining biomarkers and clinical phenotypes, distinguish
‘typical’ [i.e., memory-led AD) from ‘atypical’ AD. The
latter comprises visual/biparietal (posterior cortical atrophy
(PCA)] [64], logopenic (language), frontal (behavioral)
variants of AD [65], and cerebral amyloid angiopathy
(CAA) [66, 67]. Though each of these syndromes is vari-
ably associated with clinical presentations of non-AD
dementias, typical and atypical AD share the same core
pathology and can thus be diagnosed by the three core AD
CSF biomarkers [68].
Future cerebrospinal fluid biomarkersfor Alzheimer’s disease (differential) diagnosis
New biomarkers for differential dementia diagnosis
As mentioned before, there is an overlap in Ab1-42 val-
ues between AD and non-AD dementia patients. To
overcome this, other CSF biomarkers like Ab1-40 are
Acta Neurol Belg (2017) 117:591–602 595
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introduced to increase clinical diagnostic accuracy.
Nevertheless, Ab1-40 is also decreased in non-AD
dementia patients, which may be explained by disease
specific inter-individual variability in Ab metabolism
(high or low Ab production and/or clearance). Therefore,
the addition of the most abundant Ab isoform, i.e., Ab1-
40 into an Ab1-42/Ab1-40 ratio, might prove to be an
efficient way to diminish inter-patient variability (to
control for high or low Ab1-42 production, irrespective of
AD pathology) [69]. Ab1-40 has already been shown to
improve differential dementia diagnosis in patients with
intermediate P-tau181 levels [57]. Increased concordance
between amyloid markers (amyloid-PET scan and CSF
Ab) was found in two studies when the Ab1-42/Ab1-40
ratio was applied compared to a CSF Ab1-42 concentra-
tion alone [70, 71].
DLB and other synucleinopathies, including PD, PD
dementia, and multiple system atrophy, are characterized
by the accumulation of the protein a-synuclein in Lewy
Bodies or glial cytoplasmic inclusions [40, 72, 73].
Although the CSF biomarkers Ab1-42, T-tau, and P-tau181
have an added diagnostic value for the differential
dementia diagnosis, there is a need for additional markers
due to often existing co-pathology in, for instance, DLB
that limits the use of the AD core biomarkers for differ-
ential diagnosis [62]. As a-synuclein is the main com-
ponent of Lewy bodies, it has been assessed as a
biomarker for DLB [72–75]. Further research into the
power of a-synuclein as a differential dementia diagnosis
biomarker should clarify its potential. Furthermore, Ab1-37
and Ab1-38 increase the accuracy to differentiate AD from
FTD or DLB [69] and also, transactive response DNA
binding protein 43 (TDP-43), the main disease protein
component in ubiquitin-positive, tau-, and a-synuclein-
negative cytoplasmic inclusions in FTD and amyotrophic
lateral sclerosis (ALS) [76]. However, TDP-43 inclusions
have also been found in AD, even with a frequency of
56% in one neuropathologically confirmed AD case series
[77]. Its potential as a CSF biomarker remains to be
determined. Another promising new biomarker is total
CSF prion protein (t-PrP), to differentiate AD from CJD.
Although typical AD and CJD are clinically distinguish-
able, atypical AD phenotypes may present with similar
features as CJD, such as very high levels of T-tau in CSF.
It has been shown that t-PrP levels are lower in CJD and
increased in AD compared to controls, both for clinical
and neuropathological confirmed cases [78]. Furthermore,
in cases where 14-3-3 protein was indicative for CJD,
increased levels of t-PrP reduced the number of false
positive cases amongst AD patients. T-PrP thus has the
potential to increase diagnostic accuracy in atypical AD
patients [78].
Cerebospinal fluid biomarkers that predict
Alzheimer’s disease progression
Although the previously described markers have a high
diagnostic value, they lack the power to predict disease
progression, as they only reflect the neuropathology of AD,
reaching their maximum change at the MCI stage. There-
fore, synaptic proteins, as markers for synaptic dysfunc-
tion/loss, are investigated as candidate markers for AD
progression. The post-synaptic protein neurogranin is such
a potential biomarker [79, 80]. It has been shown that
neurogranin in CSF, but not plasma, was increased in AD
and positively correlated with CSF tau [81]. There was a
negative relationship between CSF neurogranin (and tau)
and CSF Ab1-42/Ab1-40 [81]. De Vos and coworkers were
the first to show that the CSF neurogranin/BACE1 ratio,
reflecting post-synaptic/pre-synaptic integrity, is related to
cognitive decline [82], emphasizing the potential of neu-
rogranin as an AD stage marker.
Discussion
Early diagnosis or timely diagnosis?
Recent advances in CSF analyses and other biomarkers
now enable the detection of AD in its pre-clinical phase.
This fuels the debate on how and when AD should be
detected, knowing that (1) effective disease-modifying
drugs are currently not available and (2) there are differ-
ences in the interests and needs of individual patients
(society vs research). The individual is often best served by
a timely diagnosis, which could be in the MCI phase or at
the ‘right’ moment for the individual, while the society
may benefit from population screening when pharmaco-
logical prevention of AD is available [51]. In the absence
of disease-modifying drugs, screening is debatable and
more interest may be put in case finding (screening of a
subgroup of the general population based on the presence
of AD risk factors).
For (counseling in) clinical practice as well as for
(clinical) research, CSF biomarkers are of importance to
identify those MCI subjects who are not suffering from
AD. For (clinical) research purposes, it is important to
identify (asymptomatic) subjects who are at risk to develop
AD, which is possible through Ab biomarkers as amyloid
changes are the first that occur within the AD continuum.
By follow-up of at risk subjects, testing of new screening
techniques could be performed, which should ultimately
lead to a sensitive and non-invasive screening instrument.
Indeed, a disadvantage of CSF biomarkers is that an LP is
needed, which is invasive and might lead to post-LP
596 Acta Neurol Belg (2017) 117:591–602
123
complications. Imaging biomarkers might overcome this
limitation as these are less invasive and will result in fewer
post-procedure complications. At this moment, research
should focus on the development/optimization of cost-ef-
ficient screening tools to be able to identify people in the
asymptomatic phase once disease-modifying drugs become
available. Partly due to the advance in detection tech-
niques, research for potential disease-modifying treatments
has changed its focus from the dementia phase to the MCI
phase [83] and currently also to the pre-clinical phase of
AD [51].
Evidence-based clinical indications for application
of the Alzheimer’s cerebrospinal fluid biomarker
panel
The clinical indications to analyze CSF biomarkers are (1)
neurochemical confirmation of AD in case of clinical AD
(increase diagnostic accuracy, which is especially but not
solely needed in case of early onset), (2) neurochemical
confirmation of AD in case of doubt between AD dementia
and non-AD dementia (including DLB, FTLD, VaD, and
CJD), (3) neurochemical confirmation of prodromal AD in
case of MCI, (4) neurochemical confirmation of AD in case
of psychiatric disorders (like depression or psychosis), and
(5) to rule out AD when this is clinically indicated. Over
the past 10 years, the clinical indications for referral
showed a shift from neurochemical confirmation of AD in
case of clinical AD to differential dementia diagnosis in
case of doubt between AD and non-AD dementias, pro-
dromal AD cases, and in case of ambiguous dementia
diagnosis [29, 49].
Conclusions (Table 2)
The past decade, a lot of progress has been made with
regard to standardization and harmonization of existing
biomarkers for AD, dealing with pre-analytical, analytical,
and post-analytical aspects. One of the most important
recommendations with a significant effect on pre-analytical
variability concerns the standardization of the vial in which
CSF is collected and shipped to the reference lab.
The validated core AD CSF biomarkers have an added
value in the (early, differential) diagnosis of AD and
related disorders, including mixed pathologies, atypical
presentations of AD, and in case of ambiguous dementia
diagnosis. Analysis of the core AD CSF biomarkers is a
second line diagnostic tool and should not be routinely
performed in the diagnostic work-up of dementia, except in
case of early-onset dementia. The AD CSF biomarker
panel cannot be used to confirm clinical diagnosis of non-
AD dementias, but should be used to confirm or exclude
the diagnosis of AD. The AD CSF biomarkers are of great
help to select subjects for clinical trials with potentially
disease-modifying drugs against AD and can thus even be
used to identify asymptomatic subjects who are at risk to
develop symptoms of AD.
Table 2 Recommendations for applying the core AD CSF biomarkers Ab1-42, T-tau, and P-tau181, for clinical diagnosis
Perform
CSF analysis
New
CSF biomarkers
Suspected AD diagnosis
Early-onset dementia Yes
No doubt in clinical diagnosis No
Ambiguous clinical diagnosis Yes
Early AD diagnosis
Pre-clinical AD
Clinical research Yes
Cognitively healthy elderly No
Prodromal AD
Clinical evidence for cognitive decline Yes
Differential dementia diagnosis (AD versus non-AD dementia) Yes Ab1-42/Ab1-40, t-PrP, Ab1-37, Ab1-38, a-synuclein
Mixed dementia pathology diagnosis
AD as co-pathology No
AD versus AD–CVD Yes
Atypical AD diagnosis
Diagnose atypical AD variants Yes
Ab b-amyloid, AD Alzheimer’s disease, CSF cerebrospinal fluid, CVD cerebrovascular disease, non-AD other dementia than AD
Acta Neurol Belg (2017) 117:591–602 597
123
Compliance with ethical standards
Conflict of interest This research was in part funded by the EU/
EFPIA Innovative Medicines Initiative Joint Undertaking (EMIF
Grant No. 115372); the University Research Fund of the University of
Antwerp; the Flemish Impulse Financing of Networks for Dementia
Research (VIND); and unrestrictive research grants from Janssen
Pharmaceutica NV and ADx Neurosciences. Sebastiaan Engelborghs
has received unrestricted research grants from Janssen Pharmaceutica
NV and ADx Neurosciences (paid to institution). Ellis Nie-
mantsverdriet, Sara Valckx, and Maria Bjerke report no conflict of
interest.
Ethical approval This article does not contain any studies with
human participants or animals performed by any of the authors.
Informed consent None.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://crea
tivecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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